| Objective:Traditional Chinese medicine has obvious advantages in the treatment of liver injury caused by anti-tuberculosis chemotherapy.There are a large number of clinical reports and various treatments,but there is a lack of systematic evaluation and mining.This study intends to make a systematic review and data mining on the literature of TCM Intervention on liver injury caused by anti-tuberculosis drugs at home and abroad in recent years,and summarize the TCM syndrome differentiation and treatment rules of TCM Intervention on liver injury caused by anti-tuberculosis drugs chemotherapy,so as to provide reference for clinical medication.At the same time,the data mining screening and experimental validation screening were combined to conduct high-throughput screening and validation on the data mining results,further screening active drugs and ingredients,and explore the construction of a new mode of liver protection drug screening.Method:1.The effectiveness and safety of traditional Chinese medicine intervention on liver injury induced by anti-tuberculosis chemotherapy were systematically evaluated.We searched CNKI,Wanfang,CBM,Duxiu,VIP,PubMed,web of science and other databases to search the randomized controlled trials of anti-tuberculosis chemotherapy liver injury by medical treatment.The retrieval period was from the establishment of the database to October 15,2019.Meta analysis was performed by Revman 5.3 software after data were extracted and the risk of bias was evaluated.2.The clinical reports,experimental studies,dissertations and academic monographs about the intervention of traditional Chinese medicine on liver injury caused by anti-tuberculous drug chemotherapy in the above databases were collected.The methodological quality of the included studies was evaluated and screened,and the prescription data were extracted.The retrieval time was from the establishment of the database to October 15,2019,and the literature database of liver protection prescriptions was constructed.The traditional Chinese Medicine Inheritance assistant platform system(v2.5)was used for data mining.Based on complex system entropy clustering and other unsupervised data mining methods,the data were analyzed.The core prescriptions of anti-tuberculosis chemotherapy liver injury were obtained.3.Tuebingen strain zebrafish were treated with 8 mmol/L isonazid for 72h,and the mortality rate,malformation rate and liver morphological changes of zebrafish were observed 72hpe(hour post exposure)after the addition of zebrafish,and the model of liver injury induced by anti-tuberculous drugs was established.The reliability and applicability of the model were verified by using diammonium glycyrrhizinate at different concentrations.Again will spend high frequency drug screening:different concentrations of Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.,Salvia miltiorrhiza Bge.,Curcuma wenyujin Y.H.Chen et C.Ling,Atractylodes macrocephala Koidz.,and the core prescription(Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.)and isoniazid combination,respectively dealing with zebrafish to grow to 72 h,72 hpe observation of zebrafish mortality and malformation rate and liver morphological changes.After initial screening,the optimal liver protection concentration of each drug to be screened was obtained,which was further verified by using CZ320 liver-specific fluorescent labeling of zebrafish.Result:1.A total of 15 RCTs involving 1282 patients were included.Compared with conventional liver protection therapy,the effective rate of TCM Intervention on liver injury induced by anti-tuberculosis chemotherapy[RR=1.82,95%CI(1.46,2.27),P<0.01],ALT[MD=-51.06,95%CI(-54.50,-47.63),P<0.01],AST[MD=-64.51,95%CI(-75.82,-53.20),P<0.01],TBiL[MD=-10.87,95%CI(-13.40,-8.33),P<0.01]were better than the control group Group.2.A total of 340 prescriptions were included,involving 225 kinds of drugs,with a total frequency of 3810 times.1)The first three types of Chinese medicine were:tonifying deficiency drugs(29.03%),clearing heat drugs(16.51%),diuretic and dampness drugs(13.65%),which reflected that tonifying deficiency,clearing heat and dampness were the most commonly used ideas in this study.The rest included promoting blood circulation and removing blood stasis,relieving exterior syndrome,regulating qi,resolving phlegm,relieving cough and relieving asthma,etc.2)In descending order of frequency,the four Qi attributes were cold medicine(55.31%),warm medicine(26.05%),flat medicine(16.30%).3)In descending order of frequency,the five flavor attributes were bitter(38.82%),sweet(31.15%)and pungent(20.36%).4)In descending order of frequency,the attributes of channel tropism are liver channel,spleen channel,heart channel,lung channel,stomach channel,gallbladder channel and kidney channel.It can be seen that the location of liver injury caused by anti-tuberculous chemotherapy is mainly in the liver and spleen,and the kidney will be involved after a long time.5)According to the descending order of frequency,the high-frequency drug pairs were:Radix Bupleuri,Radix Paeoniae Alba,Radix Bupleuri Poria cocos,Radix Bupleuri Radix Glycyrrhizae,Radix Bupleuri Herba Artemisiae Scopariae,Radix Bupleuri radix salviae miltiorrhizae,Radix Bupleuri radix curcumae,etc.The commonly used drug pairs are:Jiebiao Buxu drug pair,Jiebiao Lishui Shenshi drug pair,Jiebiao Huoxue Huayu drug pair,Buxu Buxu drug pair,Jiebiao Qingre drug pair.It reflects the characteristics of using Bupleurum to soothe the liver and relieve depression under the principles of tonifying deficiency,clearing heat and promoting dampness.6)Association rules revealed the core drug combination of this study is:Radix Bupleuri,Poria cocos,Radix Paeoniae Alba,Radix Glycyrrhizae,Herba Artemisiae Scopariae.7)Based on the entropy clustering algorithm of complex system,six pairs of core combinations are obtained to form six new squares.3.The experimental screening results showed that compared with the blank control group,the abnormality rate and mortality rate of Tuebingen strain zebrafish in the 8mmol/L isoniazid administration group were significantly increased,and the morphology showed loss or reduction of swim bladder,yolk sac absorption stagnation,pericardial edema and spinal curvature.With the increase of diammonium glycyrrhizinate concentration,the malformation rate and mortality rate of zebrafish decreased significantly,and the malformation rate increased slightly at high concentration,and the morphological development was normal.Therefore,in this study,8mmol/L isoniazid was used for 72h to establish a zebrafish isoniazid liver injury model.With the increase of drug concentration,the malformation rate and mortality rate of juvenile zebrafish in the isomiazid liver injury model under the intervention of Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.,Salvia miltiorrhiza Bge.,Curcuma wenyujin Y.H.Chen et C.Ling,Atractylodes macrocephala Koidz.and the core prescription(Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.)were significantly decreased.The rate of malformation and mortality increased slightly when each drug was given at high concentration.In morphology,all drug screening groups developed better than model group.The optimal concentrations of Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.,Salvia miltiorrhiza Bge.,Curcuma wenyujin Y.H.Chen et C.Ling,Atractylodes macrocephala Koidz.and the core prescription(Bupleurum chinense DC.,Poria cocos(Schw.)Wolf.,Paeonia lactiflora Pall.,Artemisia capillaris Thunb.,Glycyrrhiza uralensis Fisch.)combined to interfere with isoniazid liver injury model of juvenile zebrafish were 100,400,200,100,100,100,100,200,200,200,100μg crude drug/mL,respectively.The liver protection effect of low dose and high dose water extract at the optimum concentration decreased.In the liver injury model verification of CZ320 liver fluorescent zebrafish,compared with the blank control group,the liver fluorescence area and fluorescence light density of zebrafish in model group were significantly decreased.Compared with model group,liver fluorescence area and fluorescence optical density of zebrafish in the group to be screened were significantly increased.Conclusion1.System evaluationThe current evidence has proved that liver protection therapy of traditional Chinese medicine is more conducive to alleviate and control the liver damage caused by anti-tuberculosis chemotherapy,which is of great significance to ensure adequate and regular chemotherapy for tuberculosis patients,control the disease and successfully complete the anti-tuberculosis chemotherapy program.Limited by the number and quality of randomized controlled trials,more high-quality studies are needed to support the above conclusions.2.Data miningAccording to the results of data mining,the etiology and pathogenesis of liver injury caused by anti-tuberculosis chemotherapy should be as follows:tuberculosis first,the location of the disease first in the lung,drug poisoning after chemotherapy,the location of the disease mainly in the liver and spleen,and the disease will affect the kidney for a long time.This deficiency is marked by excess,which is marked by drug toxicity,damp heat,qi stagnation and blood stasis,and deficiency of Qi and blood in liver,spleen,lung and kidney.The general principle of treatment is tonifying deficiency,clearing heat and promoting dampness.Shugan Jieyu,Jianpi Yangxue,Qingli damp heat as the basic treatment,both Huoxue Huayu,Liqi Huatan,cough and asthma.The core drug combination of this study is:Radix Bupleuri,Poria cocos,Radix Paeoniae Alba,Radix Glycyrrhizae,Herba Artemisiae Scopariae.In this study,six new prescriptions were obtained by unsupervised entropy hierarchical cluster analysis,which are not in conflict with the general principles of tonifying deficiency,clearing heat and diuresis,and each has its own emphasis on treatment.The next step is to further verify the new prescriptions through pharmaceutical and clinical experiments.3.experiment screeningBased on data mining technology,the combination of high-frequency drugs and core prescriptions of traditional Chinese medicine intervention on liver injury caused by anti-tuberculous chemotherapy showed a certain hepatoprotective effect in zebrafish juvenile isoniazid liver injury model.This study verified the reliability and applicability of data mining technology to a certain extent,combined literature data mining screening with pharmacological experiment verification screening,explored and constructed a new model of drug screening. |
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